In the 21st century, adenovirus (Ad) ocular infections remain a significant worldwide problem for which there are no antiviral treatment options. One long term objective is to develop an effective topical antiviral to treat adenoviral ocular infections. In this competing renewal, we will evaluate several promising antivirals (ddC, NCT, CPE-C) in vitro and in our rabbit ocular model and determine the best candidate for clinical development. The issue of emerging resistance to candidate antivirals will be addressed and the possibility of clinically-significant cross resistance among antivirals will be assessed following the determination of their respective molecular mechanisn(s) of inhibitory action. Finally, we will characterize the role of local innate immunity that initially protects the eye from infection by adenovirus. Specifically, we will evaluate the role of defensin-like compounds including alpha and beta defensins, defensin-like chemokines (CXCL 10 and CXCL 11), and cathelicidins. The results of these pathogenesis studies will advance our knowledge of how adenovirus overcomes host defenses to successfully establish eye infections. In summary, the development of an effective antiviral treatment should lessen patient misery, limit epidemics, and reduce economic, educational and other societal losses from absenteeism. Furthermore, a better understanding of antiviral resistance and the innate immune host defenses will enable us to optimize our therapeutic options against this significant ocular pathogen.